We propose to study novel imaging sensors composed of a semiconducor material known as Cadmium Zinc Telluride (CZT), and incorporate these sensors into an innovative configuration for an advanced Positron Emission Tomography (PET) system designed for imaging small laboratory animal cancer models. The next generation of discoveries in molecular cancer imaging assay research require PET instruments with an order of magnitude higher sensitivity for visualizing and quantifying very low concentrations of molecular probe targeting subtle molecular-based cancer processes. In order to realize this goal, new PET instruments must provide enhanced 511 keV photon coincidence detection efficiency, spatial, energy, and coincident time resolutions, and count rate performance all at once. The most sensitive high resolution PET systems use photon detectors comprising scintillation crystals coupled to photomultiplier tubes. However, these systems still have relatively low (~3%) coincidence photon detection efficiency and the scintillation detectors have relatively inefficient conversion of the 511 keV energy into an electronic signal, especially for high resolution designs that utilize miniscule (<2 mm wide) scintillation crystal elements and fiber optic coupling. Low 511 keV photon detection efficiency and weak crystal light signals degrade many of the crucial performance parameters in PET, such as spatial and contrast resolution and quantitative accuracy that are important for molecular probe sensitivity. The proposed compact CZT detector configuration together with the 3- dimensional (3D) interaction localization capabilities yield an order of magnitude better coincidence detection efficiency (~20%), which will enable sufficient counts collected to reconstruct images at the desired 1 mm3 spatial resolution with a relatively short data acquisition time. The proposed superior energy resolution (<3% at 511 keV) allows efficient rejection of random and scatter background to achieve high contrast and quantitative accuracy without compromising photopeak window counts. Finally, 3D event positioning in the proposed CZT detectors is set electronically by an electrode pattern, rather than by cutting miniscule crystals, significantly simplifying construction. If successful, the capabilities of PET to detect, visualize and quantify low concentrations of molecular cancer probe will be enhanced substantially, which would impact the development of new cancer imaging assays and help to guide discovery of novel treatments for cancer.